Method for the preparation of prostaglandin intermediates from a mold metabolite

ABSTRACT

This invention provides intermediates which are essential for a new chemical method which converts terrein, a fungal metabolite, to an intermediate which is known to be useful for the preparation of prostaglandins of the C series and analogs of other prostaglandins.

BACKGROUND OF THE INVENTION

This application is a continuation-in-part of our earlier filedapplication, U.S. Ser. No. 611,468, filed Sept. 8, 1975, now abandoned.

DETAILED DESCRIPTION OF THE INVENTION

The natural prostaglandins are unsaturated fatty acid derivativespossessing a cyclopentane ring and several oxygen functions and doublebonds. They have been detected in most mammalian tissues and arecharacterized by intense physiological activity. Among the significantproperties which they exhibit and which have actual or potentialclinical application are the regulation of fertility, the termination ofpregnancy, regulation of blood pressure, inhibition of plateletaggregation, regulation of the bronchial airway diameter, mediation ofthe inflammatory response, control of gastric secretion, and so on. Inactual clinical use at the moment are prostaglandins E₂ and F₂α.

Tissues of higher animals and their excreta are not rich enough inprostaglandins to serve as a significant source for large scaleproduction. The sea whip, Plexaura homomalla, is the richest naturalsource now known but harvesting, processing and chemical transformationof prostaglandins from this source is labor intensive, subject tobiological variation and time and seasonal influences. Biosynthesisusing mammalian enzymes has been used for the preparation of significantamounts of the prostaglandins, but is inadequate to supply world needsand is no longer a primary method of production. Many totally syntheticmethods have been described, many of considerable ingenuity, and some ofthese are now utilized for the commercial production of prostaglandins.These methods all start with optically inactive starting materials and,because the natural prostaglandins are optically active, an essentialstep in these methods is the resolution of a key intermediate. Thisentails the loss of at least 50% of the material as representing theunnatural and undesired (except for specialized purposes) enantiomer.Alternatives use living microorganisms as sources of enantioselectiveenzymes. The greater efficiency of carbon yield of these processes ispartially offset by the added labor required. Other attempted solutionsto this problem involve the use of expensive asymmetric reagents.

Essential to our inventive process is the use of a convenientlyavailable fungal metabolite, terrein, which has the correct absolutestereochemistry for conversion to the natural prostaglandins without thenecessity of optical resolution at any stage of the process.Furthermore, the chemical structure of terrein is such that usefulfunctional groups are present in the molecule in strategic places forthe elaboration of the necessary functional groups and molecularfeatures characteristic of the natural prostaglandins. Additionally, themolecule contains sufficient novel features so that the process may bemodified at various steps in the synthesis to produce useful artificialanalogs of the prostaglandins. pg,4

According to one aspect of the invention, terrein is converted tocyclopentenes of the formula ##STR1## wherein R is --CH═CHCHO,--CHOH--CHOH--CH₃, --CH═CHCH₃, or --CH═CH--CR₅ (CH₂)₄ CH₃ with R₅ being═O or ##STR2## R₁ is part of the double bond of said cyclopentene or R₆; R₂ is the same R₆ as in R₁ ; R₃ is ═O, ##STR3## R₄ is hydrogen, partof the double bond or forms, together with R₃, a γ-lactone of theformula --CH₂ --CO--O--; R₆ is a protective ester group that can beremoved chemically without adverse effect on the other substituents ofsaid cyclopentene; and R₇ is a loweralkyl moiety.

In essence, the above cyclopentenes are all derived from terrein, whichis essential in the preparation of the γ-lactone of formula ##STR4##This is a known compound which has been used for making the bioactiveprostaglandin C₂ as described by Kelly et al. in Prostaglandins, Volume4, page 653 ff. (1973).

The new intermediates which are part of the above formula forcyclopentenes are best identified by reference to the following flowdiagrams which show the sequence in which they are made and used. Theflow diagrams both start with the known compound terrein and lead to thecompound of Structure II shown above.

Conceptually, conversion of terrein to, for example, prostaglandin E₂requires four essential steps arranged in a suitable sequence: (1) theintroduction of the C₇ side chain with loss of the double bond in thecyclopentenone ring; (2) the introduction of an appropriate oxygen atom,(3) the addition of a 5-carbon aliphatic chain to complete the lower C₈side chain, and (4) the removal of the "extra" hydroxyl group.

More specifically, the current invention is exemplified by the followingpreferred routes for the conversion of terrein to the knownprostaglandin C₂ intermediate II:

It will be understood by those skilled in the art that in the case whereR₅ in side chain R includes the hydroxy group, any number of protectivegroups may be used to temporarily replace the hydrogen in said -OH. Thefollowing diagrams exemplify this with the tetrahydropyranyl group,although t-butoxy or tetrahydrofuranyl and other protective groups thatcan be removed by treatment with mild acids are equally suitable.##STR5##

In a general embodiment, terrein conveniently obtained in quantity andin a very pure state, as reported in the literature by fermentation ofAspergillus terreus [Misawa et al., Nippon Nogeikagaku Kaishi, 36,699(1962)], is converted to its dibenzoyl ester using one of the well knownstandard means of esterifying an alcohol. For instance, terrein isdissolved in an inert solvent, such as dry tetrahydrofuran, andcontacted with an organic acid anhydride and sodium acylate, or with anacid chloride and sodium acylate or, less advantageously, with the acylanhydride or acyl chloride and an amine such as triethylamine orpyridine, or by using the free acid and dicyclohexylcarbodiimide and thelike. The reaction takes place at a temperature between room temperatureand the boiling point of the solvent, with some heating preferred inorder to minimize formation of the mono ester and to speed the rate ofreaction. Obviously, a wide variety of mono- and diesters resulting fromthe use of a variety of acids may be prepared by simple manipulation ofreaction conditions in the manner chemists usually employ.

In the case of R₆ being benzoyloxy, the dibenzoate (1) is converted to aglycol (2) using, preferably, osmium tetroxide-barium chlorate mixturesin a reaction inert solvent such as aqueous dioxane. Chemists skilled inthe art will recognize that alternate means of preparing such glycolsmay be employed such as, for example, the use of osmium tetroxide inequivalent quantities, the use of osmium tetroxide in catalyticquantities, as above, but with periodate instead of chlorate, the use ofalkaline hydrogen peroxide, the use of hydrogen peroxide in the presenceof ferrous sulfate (Fenton's reagent) or of tungstic acid, or the use ofiodine and silver benzoate (Prevost's reagent), or the use of iodine andsilver acetate in wet acetic acid, and the like. For purposes ofcharacterization, the glycol grouping can be protected and derivatizedas the acetonide or a variety of esters. The keto function of glycol (2)is then reduced to the alcohol (3) using known reducing agents of whichzinc borohydride and 1-selectride work efficiently. THF is a goodsolvent for the reduction, but, of course, a wide variety of othersolvents and other reducing agents can be employed including the familyof alkali metal borohydrides, hydrogen gas with a catalyst,aluminohydrides and so on. The glycol grouping is cleaved to produce thealdehyde (4) by oxidation with sodium periodate in a reaction inertsolvent such as aqueous dioxane or THF. Alternately, lead tetraacetatecan be employed.

The periodate reaction is facilitated by the use of biphasic solventmixtures of which water and ether is effective. The lower (C₈) sidechain of the prostaglandins is then introduced by the use of a Wittigreagent such as the sodium salt of dimethyl-2-oxoheptylphosphonate in adry solvent, such as THF. Unsaturated ketone (5) is then esterified withan acid chloride or anhydride with an activated methylene or methinegroup such as acetoacetic acid and its alkylated analogs or a malonylsemiester or one of its alkylated analogs. Preferably for the routeillustrated, ethyl malonyl chloride is used. Ester (6) can also beprepared by esterifying alcohol (4) first and then performing the Wittigreaction. The resulting ester (6) is then cyclized using a suitablebase, such as sodium hydride, potassium t-butoxide, and the like.Non-nucleophilic bases of sufficient base character to ionize the activemethylene or methine of the intermediate ester group are preferred and avariety will suggest themselves to those skilled in the art. Theseinclude triethylamine, pyridine, 1,5-diazabicyclo [4.3.0] non-5-ene,etc. Nucleophilic bases may be employed, but the yield often suffers dueto partial loss of one or more of the desired ester groups of compound(6). Under the conditions used herein, one of the benzoyl groups is lostduring the cyclization process to form intermediate (7) which isadvantageously substituted for conversion to the prostaglandin C series.Compound (7) is then converted to intermediate (8) by heating in aqueousglycerine or by hydrolysis using lithium iodide in DMF solvent with orwithout sodium cyanide added, or through the use of copper acetate inhexamethylphosphortriamide, and the like. The remaining benzoyloxy groupof (8) may be removed by a variety of reductive processes of which zincin acetic acid is one of the most highly effective. Alternate methodsfor performing this step include the use of, for example, zinc or zincamalgam in acetic anhydride, aqueous mineral acids, chromium II salts,or calcium in liquid ammonia. Care must be exercised in these reactionsto avoid reduction of the double bond of the pentene ring. Manytranspositions of the order of the steps in this sequence will suggestthemselves to those skilled in the art. These do not lie outside thescope of this invention. An example of such is reaction of ethylmalonylchloride with the free alcoholic group of aldehyde (4) followed by basecatalyzed cyclization in the manner described for the conversion of (6)to (7). Wittig reaction to introduce the lower side chain in the mannerexemplified for the conversion of (4) to (5) will then produce (7) whichmay be converted to II as before.

In another embodiment of the present invention, terrein is converted toCompound II via other intermediates. In this method, terrein isconverted to its diacetyl derivative (10) by acetylation under one ofthe many known esterification conditions of which treatment with aceticanhydride and sodium acetate is the simplest. Diacetylterrrein is thenoxidized with selenium dioxide to give conjugated ketoaldehyde (11). Theoxidation is most effectively carried out by using freshly sublimedselenium dioxide in an inert atmosphere. The aldehyde function ofcompound (11) reacts preferentially with organometallic reagents such asamyl Grignard and the like to form the lower (C₈) side chain of theprostaglandins. The alcoholic function of (12) is conveniently protectedby the use of a variety of ethers capable of subsequent convenientremoval with dilute acid of which the tetrahydropyranyl ether has beenuseful. Temporary protection is required to retain the oxygen functionin its designated position. Obviously, those skilled in the art will seethat one may also use silyl ethers or other ketals, especially thosewithout anomeric or optically active center such as those prepared from2,2-dimethoxy-propane or from gamma-pyrone derivatives and the like, inthe place of the tetrahydropyranyl ether group. Reduction of the ketofunction of ether (13) proceeds smoothly under a variety of conditionsof which the use of 1-selectride and zinc borohydride are particularlyconvenient. The newly introduced alcohol function of (14) is thenesterified in the usual way with an ester containing an active methyleneor methine function. The resulting derivative (15) can be used withoutisolation and without rigorous purification. The next step involves theremoval of the above protective function with dilute acid mixtures toproduce (16). Oxidation of (16) can be performed with a variety ofreagents of which the Jones procedure (CrO₃ /H₂ SO₄ /Me₂ CO), MnO₂, anddicyanodichloroquinone are particularly useful. Compound (17) is thencyclized with base or acid catalysts to produce the acetyl analog ofcompound (7) which then can be converted by known procedures toprostaglandin C₂ and its various analogs in a manner analogous to thatused in the first process.

Any substitution on the side chains may be made by the known chemistryof the prostaglandins. This will include a variety of aliphatic,aromatic, mixed aromatic aliphatic, branched chain or straight chainand/or side chain substitutions of oxygen and sulfur for methylene, halosubstitutions, and such other substitutions as are well known toprostaglandin chemists.

The following examples will serve to illustrate this invention withoutlimiting it thereto.

EXAMPLE 1 PREPARATION OF TERREIN DIBENZOATE (1)

Terrein (18.5g, 0.120 moles) was dissolved in molten benzoic anhydride(265g, 1.17 moles) containing 21g (0.178 moles) of sodium benzoate. Thetemperature of the melt was maintained at 55°-65°, as highertemperatures induced decomposition. After 7 hours, the reaction wascooled to room temperature, covered with ether and extracted with coldwater. Crushed ice was added to the ether layer and the extraction wascontinued with ice cold 50% (1:1) aqueous ammonium hydroxide. Theextraction was continued until no benzoic anhydride was detected by tlc(silica gel G with CHCl₃ --visualization with iodine vapor). The etherlayer was then washed with saturated NaCl solution until the washes wereneutral to hydrion paper, dried over MgSO₄, filtered and evaporated.Column chromatography on silica gel with chloroform afforded 36.0g (84%)of terrein dibenzoate (1) and 3.98g of 1-, or 2-benzoylterrein. Terreindibenzoate showed IR bands at 1745 and 1660 cm⁻¹ ; UVλ_(Max).sup. EtOH274 nm (log ε 4.37), 232 nm (log ε 4.47); pmr (CDCl₃) 1.88 (d), 5.60(d), 6.35 (m), 6.45 (s), 6.52 (d), 6.57 (m).

EXAMPLE 2 2β,3α-Dibenzoyloxy-4-(1,2-dihydroxypropyl)-cyclopent-4-ene-1-one (2)

Terrein Dibenzoate (1) (21.6g, 0.0596 moles) was dissolved at roomtemperature in 600 ml of dimethylformamide containing 50 ml of water. Tothis solution was added 1.5g (0.0059 moles) of osmium tetroxide in 20 mlof DMF (9.9 mole%). The solution turned a dark brown-black. After 5minutes of stirring with nitrogen gas passing through the reaction,9.60g (0.0298 moles) of barium chlorate dihydrate in 180 ml of water wasadded slowly over a 3-4 hour period. Before the last few ml of solutionhad been added, an aliquot of the reaction mixture was quenched inether/water and showed no starting material present by tlc (silica gelG; chf; permanganate spray). The reaction was poured into three litersof water and extracted with three 500-ml portions of ether. The etherlayers were combined, back extracted with four 1-liter portions of watersaturated with salt, and then dried over sodium sulfate for one hour.The dried ether layer (still containing the sodium sulfate) wassaturated with H₂ S gas for 10 minutes and then stirred for 30-40minutes. The solution was then filtered through celite, evaporated, andvacuum dried for 14 hours to produce a foamy resinous solid whichweighed 17.0g (72%) and was essentially pure (2) by tlc (ether): IRbands at 3400-3600 and 1745 cm⁻¹ ; UVλ_(Max) ^(EtOH) 232nm (log ε 4.64);pmr (CDCl₃) 1.22 (d), 3.37 (s), 4.17 (m), 5.5 (m), 6.5 (m), 7.45 and8.07 (m) δ.

EXAMPLE 3 1α-Hydroxy-2β,3α-dibenzoyloxy-4-(1,2-dihydroxypropyl)-cyclopent-4-ene (3)

Diol (2) (6.0g, 0.015 moles) was dissolved in 100 ml THF and added to asolution of zinc borohydride in ether so as to have a 5 mole excess.Under these conditions, a bright yellow color developed which fadedslightly with time and a white precipitate formed within 20 minutes. Ifthe precipitate was not redissolved, considerable starting material wasrecovered. The precipitate was dissolved by the addition of more THF andthe solution was stirred until an aliquot showed no more startingmaterial by tlc (ether) when worked up with ether-10% aqueous HCl. Thereaction was then cooled in an ice bath and carefully treated with 10%aqueous HcL to pH 1. Saturated salt solution (1 liter) was added and thereaction extracted with ether (4 times 150-ml portions). The extractswere combined, dried over sodium sulfate, evaporated, andchromatographed over silica gel with 0.5% EtOH in ether or 2% MeOH inchf to give the desired triol (3) (4.75g, 79% yield): IR bands3150-3650, 1740 cm⁻¹ ; UVλ_(Max) ^(EtOH) 232 nm (log ε 4.32); pmr(CDCl₃) 1.20 (m), 3.57 (m), 4.00 (m), 4.77 (s), 5.32 (t), 6.10 (m), 6.32(d), 7.42 (m) and 8.05 (m) δ.

EXAMPLE 4 1,2-Dibenzoyloxy-3-aldoxo-cyclopent-3-ene-5-ol (4)

Triol (3) was oxidized with 1 molar equivalent of sodium periodate(3.2g, 0.015 moles) using a biphasic system consisting of 1 part waterand 5 parts ether. When tlc examination showed starting material to beabsent, the reaction was diluted with water, saturated with sodiumchloride, and extracted several times with ether. The ether layers werecombined, dried over sodium sulfate, filtered and evaporated. Vacuumdrying produced a resinous solid hydroxy-aldehyde (4), 5.1g (96%): IRbands 3150-3650, 1745 and 1710 cm⁻¹ ; UVλ_(Max) ^(EtOH) 230 nm (log ε4.43); pmr (CDCl₃) 4.18 (m), 4.95 (m), 5.35 (t), 6.60 (d), 7.00 (m),7.50 (m), 8.03 (m) and 9.92 (s) δ; CIMS, MH⁺ 353.

EXAMPLE 54(S),5(S)-Dibenzoyloxy-3(R)-hydroxy-1-(3-oxo-trans-1-octenyl)-cyclopentene(5)

A 2-neck 50-ml round bottom flask (containing a magnetic stirring bar)was heated in an oven at 120°, purged with argon and then maintainedunder a positive pressure of argon. After it had cooled to roomtemperature, a 0.03047 M THF solution of the sodium salt of dimethyl(2-oxoheptyl)-phosphonate (11.2 ml, 0.341 mM, 1.20 equiv.) was injectedinto the flask. Next a solution of compound 4 (0.100g, 0.284 mM)dissolved in THF (3 ml) was injected into the flask. The resultantmixture was allowed to stir at room temperature for 45 minutes.

The reaction mixture was then diluted with ether and washed with 5% aq.HCl solution and sat. NaCl solution. The combined aqueous phases wereextracted with ether. Next the combined ethereal phases were dried (anh.Na₂ SO₄), filtered and concentrated to a pale yellow oil (0.172g).Purification of the crude product by thick-layer chromatography (silicagel G, 1:24 MeOH-CHCl₃, 2 developments) afforded compound (5) as acolorless oil (0.087 g, 68%): IR bands 3540, 1735, 1690 (sh), 1645, 1620cm⁻¹ ; pmr (CCl₄) 0.91 (t), 1.06-1.70 (br m), 2.37 (t), 3.66 (br s),4.73 (m), 5.16 (t), 6.27 (d), 6.38 (m), 7.18 (d), 7.25-8.28 (br m) δ;UVλ_(Max) ^(MeOH) 231 nm (log ε 4.48), 264 nm (log ε 4.37); CIMS, MH⁺449.

EXAMPLE 63(R)-(4(S),5(S)-Dibenzoyloxy-1-[3-oxo-trans-1-octenyl]-cyclopentenyl)ethyl malonate (6)

A solution of compound (5) (0.058g, 0.130 mM) dissolved intetrahydrofuran (1.5 ml) was transferred to a 15-ml rb flask thatcontained a magnetic stirring bar. The flask was warmed to 42°. Next0.19 ml of a 10% (v/v) solution of ethyl malonyl chloride in THF(0.0238g, 0.158 mM, 1.22 equiv.) was injected into the flask. Then 0.22ml of a 10% (v/v) solution of triethylamine in THF (0.016g, 0.158 mM,1.22 equiv.) was injected into the flask. The resultant mixture wasstirred for 1 hour at 42° before being cooled to room temperature. Etherwas then added to the reaction mixture. The mixture was washed with 10%aq. HCl solution and sat. NaCl solution. The combined aqueous phaseswere extracted with ether. Next the combined ethereal solutions weredried (anh. Na₂ SO₄), filtered and concentrated to a yellow oil.Purification of this oil by thick-layer chromatography (silica gel G,1:99 MeOH-CHCl₃) yielded compound (6) as a pale yellow oil (0.0517g,71%): IR bands 1735, 1690 (sh), 1645, 1620 cm^(-1;) pmr (CCl₄) 0.90 (t),1.05-1.70 (br m), 2.37 (t), 3.34 (s), 4.12 (q), 5.58 (t), 5.80 (m), 6.28(d), 6.33 (d), 6.41 (d), 7.17 (d), 7.21-8.19(br m) δ; UVλ_(Max) ^(MeOH)232 nm (log ε 4.46), 264 nm (log ε 4.36); CIMS, 441 (MH⁺ -benzoic acid),etc.

EXAMPLE 71(R),5(R),8(r)-benzoyloxy-4(R)-carbethoxy-6-(3-oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0] oct-6-ene (7)

A 2-neck 15-ml round bottom flask (containing a magnetic stirring bar)was heated at 120°, purged with argon and then maintained under apositive pressure of argon. After it had cooled to room temperature, asolution of compound (5) (0.057 g, 0.102 mM) dissolved in t-butylalcohol (3 ml) was injected into the flask. Next a 0.04 M solution ofsodium t-butoxide in t-butyl alcohol (0.26 ml, 0.0104 mM, 0.10 equiv.)was injected into the flask. The resultant mixture was stirred for 2.5hours at room temperature. Then the reaction mixture was warmed to 40°and stirred for an additional 3.5 hours. At the end of that stirringperiod, more of the sodium t-butoxide solution (0.52 ml, 0.0208 mM, 0.20equiv.) was added to the reaction mixture, which was then stirred at 40°for an additional 24 hours. Finally, one last portion of the sodiumt-butoxide solution (0.52 ml, 0.0208 mM, 0.20 equiv.) was added to theflask and the reaction mixture was refluxed for 16 hours. Next the rbflask was allowed to cool to room temperature and the reaction wasquenched by the addition of 10% aq. HCl solution (1 ml). The quenchedreaction mixture was concentrated to a residue, which was purified bythick-layer chromatography (silica gel G, 1:99 MeOH-CHCl₃ 2developments). Extraction of the major band afforded compound (7) as apale yellow oil (0.012 g, 27%): IR bands 1790, 1735, 1690 (sh), 1640,1620 cm⁻¹ ; pmr (CCl₄) 0.92 (t), 1.09-1.72 (br m), 2.50 (t), 3.37 (d),4.17 (br d), 4.32 (q), 5.22 (br d), 5.89 (m), 6.20 (d), 6.31 (br s),7.26 (d), 7.18-8.17 (br m) δ; UVλ_(Max) ^(MeOH) 231 nm (log ε 4.24), 262nm (log ε 4.37); chemical ionization mass spectrum or CIMS (isobutane)441 (MH⁺, 52%).

EXAMPLE 81(R),5(R),8(R)-Benzoyloxy-6-(3-oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0] oct-6-ene (8)

Compound (7) (100 mg) was suspended in a mixture of heat dried lithiumiodide (6 equivalents) and 0.5 ml of anhydrous pyridine and gentlyrefluxed under a blanket of dry nitrogen for 3 hours. The reactionmixture was cooled to room temperature and poured onto crushed ice. Theresulting mixture was extracted with chloroform, the chloroform layerswere washed with dilute HCl solution, dried and evaporated. The desired(8) was isolated by preparative tlc as an oil showing an IR band at 1770cm⁻¹ (λ-lactone), no ethyl group in the pmr, and a molecular m/e 368.

EXAMPLE 9 1(R),5(R)-6(3-Oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0]oct-6-ene (II)

Compound (8) (50 mg) was dissolved in 3 ml of glacial acetic acid, 50 mgof zinc dust was added, and the mixture was refluxed for 8 hours. Aftercooling, the mixture was diluted with 10 ml of water and extractedseveral times with chloroform. The chloroform layers were dried overanhydrous sodium sulfate, filtered and evaporated in the usual way togive 45 mg of an oil from which the desired (9) was obtained bypreparative tlc: IR bands 1760 and 1690 cm⁻¹ ; UVλ_(Max) ^(MeOH) 275 nm(log ε 4.30); CIMS, MH⁺ 249.

EXAMPLE 10 Terrein diacetate (10)

Terrein (0.0308g, 0.20 mM) was dissolved in a mixture of aceticanhydride (3 ml) and anhydrous sodium acetate (0.020g, 0.244 mM). Thereaction mixture was stirred for 21 hours at room temperature. Then theacetic anhydride was removed by distillation (0.5 mm Hg at 36°). Theresidue was dissolved in dichloromethane, filtered and concentrated toyield (10) as a viscous, pale yellow oil (0.0475g, 99.8%): IR bands3020, 2920, 1745, 1725, 1645, 1585, 1435, 1370, 1350, 1235, 1180, 1055,1035, 965 cm⁻¹ ; pmr (CDCl₃) 1.95 (d of d), 2.15 (s), 5.25 (d), 6.08(d), 6.2-6.4 (m); UVλ_(Max) ^(CHCl).sbsp.3 274 nm (log ε 4.21).

EXAMPLE 11 Terrein diacetate (10)

Terrein (6.50 g, 42.2 mM) was transferred to a 250 ml Erlenmeyer flaskthat contained acetic anhydride (50 ml) and a magnetic stirring bar. Theresultant slurry was stirred at 0°. Then a solution of anhydrousp-toluenesulfonic acid dissolved in acetic anhydride (15 ml) was addedto the flask. After 5 minutes the flask was warmed to room temperatureand the reaction mixture (which was now a pink solution) was stirred foran additional 2 hours.

The acetic anhydride was then removed by distillation (0.25 mm Hg at40°), and the residual brown oil was dissolved in ether. The etherealsolution was washed with cold (0°) 0.1 N NaHCO₃ solution and distilledwater. The solution was subsequently dried (anh. Na₂ SO₄), filtered andconcentrated to a pale yellow oil (8.813g, 88%). Examination by tlc(silica gel G, 49:1 CHCl₃ -MeOH) revealed that the product was notcontaminated with either stirring material or monoacetylated product.

EXAMPLE 12 4(S),5(R)-Diacetoxy-3-(trans-1-propenal)-2-cyclopenten-1-one(11)

Terrein diacetate (10) (14.09g, 59.1 mM) was transferred to a 1 literround flask that contained a magnetic stirring bar. The startingmaterial was dissolved in 500 ml of xylene, and this solution was thenrefluxed with stirring. Next freshly resublimed selenium dioxide (9.19g,82.8 mM, 1.40 equiv.) was added in small portions to the reactionmixture, and a Dean-Stark trap (for removal of water) was insertedbetween the flask and the reflux condenser.

After 4.5 hours a second portion of SeO₂ (9.19 g) was added to theflask. Four hours later, refluxing was stopped and the hot reactionmixture was filtered. The red filtrate was concentrated to a black oil(14.140 g). Examination by tlc (silica gel G, 1:24 MeOH-CHCl₃) revealedthat this oil contained at least 6 components. The desired product (11)gave an immediate positive test with 2,4-dinitrophenylhydrazine sprayreagent. The crude reaction product was charged to a 250g silica gelcolumn, which was developed rapidly with CHCl₃. The fractions whichcontained aldehyde (11) were combined to yield a red oil (8.05g). Thisproduct was further purified by the use of silica gel (250g) columnchromatography again (CHCl₃ as the eluting solvent) to afford compound(11) as a pale yellow oil (4.41g, 30%).

The desired product (11) was characterized by the following spectraldata: IR bands 3020, 2920, 2820, 2720, 1745-1735 (broad), 1688, 1570,1370, 1230, 1170, 1110, 1035, 970 cm⁻¹ ; pmr (CDCl₃) 2.14 (s), 5.21 (d),6.15 (d), 6.52 (d of d), 6.69 (s), 7.37 (d of d), 9.70 (d of d);UVλ_(Max) ^(CHCl).sbsp.3 274 nm (log ε 4.19), 284 nm (sh, log ε 4.11);CIMS, MH⁺ 253 (100%) and 193 (54%, MH⁺⁻ HOAc).

EXAMPLE 134(S),5(R)-Diacetoxy-3-(3-hydroxy-trans-1-octenyl)-2-cyclopenten-1-one(12)

A 2-neck 50-ml round bottom flask containing a magnetic stirring bar washeated in an oven at 120°, purged with argon and then maintained under apositive pressure of argon. After the flask had cooled to roomtemperature, a solution of 1-bromopentane (0.889g, 5.89 mM, 1.26 equiv.)dissolved in tetrahydrofuran (3.5ml) was added by injection. Then astrip of magnesium ribbon (0.156g, 6.41 mM, 1.38 equiv.) was transferredto the flask.

since formation of the Grignard reagent proceeded exothermically, thetemperature of the flask was moderated using a beaker of water at roomtemperature. After 30 minutes of stirring, another 3.5-ml. portion ofTHF was injected to dissolve the white precipitate which had formed.Thirty minutes later, 3.5-ml. of ether was injected into the flask,which was then cooled to -78°.

Next a solution of the starting aldehyde (11) (1.175g, 4.66 mM, 1.0equiv.) dissolved in a mixture of THF (3.5 ml) and Et₂ O (3.5 ml) wasinjected into the flask. The resultant brown slurry began to solidify.Solidification was avoided by the use of vigorous stirring and theinjection of more ether (4 ml). The reaction mixture was stirred for anadditional 3.5 hours at -78°. The mixture was then poured into a rapidlystirring 10% aq. HCl solution. The ethereal layer was removed and theaqueous layer was extracted with ether. The combined ethereal phaseswere dried (anh. Na₂ SO₄), filtered and concentrated to a brown oil(1.297 g).

The crude reaction product was purified by silica gel (130 g) columnchromatography (1:24 MeOH-CHCl₃ as the eluting solvent mixture) to yielda mixture of the two epimeric alcohols (12). The purified product was apale yellow oil (0.779 g, 52%): IR bands 3700-3460 (broad), 2920, 2840,1745, 1725 (sh), 1638, 1580, 1370, 1095, 980 cm⁻¹ ; pmr (CDCl₃) 0.90(t), 1.10-1.70 (br m), 2.14 (s), 2.15 (s), 2.57 (br s), 4.16-4.40 (m),5.22 (d), 6.09 (d), 6.20-6.35 (m); UVλ_(Max) ^(CHCl).sbsp.3 272 nm (logε 4.22).

EXAMPLE 144(S),5(R)-Diacetoxy-3-(3-[2-tetrahydropyranyloxy]-trans-1-octenyl)-2-cyclopenten-1-one(13)

Compund (12) (0.050g, 0.154 mM) was transferred as a neat liquid to a5-ml round bottom flask which contained a magnetic stirring bar. Thisstarting material was dissolved in ether (0.25 ml). Next dihydropyrane(0.02 ml, 0.019 g, 0.232 mM, 1.5 equiv.) was added to the flask. Then asolution of p-toluenesulfonic acid (0.0016g, 0.0092 mM, 0.06 equiv.)dissolved in ether (0.25 ml) was transferred to the reaction flask.

The reaction mixture was stirred for 2 hours at room temperature, duringwhich time the color of the mixture changed from pale yellow to brown.Then sat. NaHCO₃ solution and more ether were added to the flask. Afterthe aqueous phase was removed, the ethereal phase was washed with sat.NaHCO₃ solution, distilled water and sat. NaCl solution. Next theethereal phase was dried (anh. Na₂ SO₄), filtered and concentrated toyield a brown oil (65.7 mg). Purification of the crude product by thicklayer chromatography (silica gel G, 1:32 MeOH-CHCl₃) afforded THP-ether(13) as a pale yellow oil (44.2 mg, 70%): IR bands 3000, 2940, 2860,1745, 1730 (sh), 1640, 1465, 1450, 1440, 1375, 1240, 1125, 1080, 1025,970 cm⁻¹ ; pmr (CDCl₃) 0.89 (t), 1.10-1.55 (br m), 1.63 (m), 2.13 (s),2.15 (s), 3.4-4.2 (m), 4.58 (br s), 5.20 (d), 6.09 (d), 6.16-6.20 (m);UVλ_(Max) ^(CHCl).sbsp.3 274 nm (log ε 4.20), 326 nm (sh, log ε 3.23 ).

EXAMPLE 154(S),5(S)-Diacetoxy-1-(3-[2-tetrahydropyranyloxy]-trans-1-octenyl)-cyclopenten-3-ol(14)

A 2-neck 15-ml round bottom flask containing a magnetic stirring bar washeated in an oven at 120°purged with argon and then maintained under apositive pressure of argon. After it had cooled to room temperature, asolution of ketone (13) (0.052g, 0.127 mM) dissolved in tetrahydrofuran(1.1 ml) was injected into the flask. The flask was then cooled to -78°.

Next 0.14 ml of a 1.107 M solution of lithium tri-sec-butylborohydride(obtained from Aldrich under the name of "1-selectride") (0.155 nM, 1.22equiv.) was injected dropwise into the flask. This addition caused thecolor of the reaction mixture to change from pale yellow to yellowishbrown. After 2 hours of stirring at -78°, a 10% aq. HCl solution (0.1ml) was injected into the flask. The flask was allowed to warm to roomtemperature and then more HCl solution (8 drops) was added to adjust thereaction mixture to pH 6. The final acidification caused the color ofthe reaction mixture to change to pale yellow. After the acidifiedreaction mixture had stirred at room temperature for an additional 45minutes, ether and distilled water were added. The aqueous phase wasremoved and then the ethereal phase was washed with water and sat. NaClsolution. Next the ethereal phase was dried (anh. Na₂ SO₄), filtered andconcentrated to a pale yellow oil (69.5 mg). Purification of the crudeoil by thick layer chromatography (silica gel G, 1:24 MeOH-CHCl₃)yielded the reduced product (14) as a pale yellow oil (37 mg, 71%): IRbands 3640-3300 (broad), 2920, 2855, 1735, 1450, 1370, 1125, 970 cm⁻¹ ;pmr (CDCl₃) 0.89 (t), 1.09-1.52 (br m), 1.63 (m), 2.06 (s), 2.09 (s),2.78-3.05 (br s), 3.3-4.2 (m), 4.57 (br s), 5.15-6.22 (br m) δ;UVλ_(Max) ^(CHCl).sbsp. 3 236 nm (log ε 3.84); CIMS, 393 (MH⁺ -H₂ O).

EXAMPLE 163-(4(S),5(S)-Diacetoxy-1-[3-hyddroxy-trans-1-octenyl]-cycloentenyl)ethyl malonate (16)

Alcohol (14) (0.0285g, 0.0694 mM) was transferred to a 15-ml roundbottom flask that contained a magnetic stirring bar. Tetrahydrofuran(0.8 ml) was added to the flask and, after the starting material haddissolved, the flask was cooled to 0° C. Next 0.10 ml of a 10% (v/v)solution of ethyl malonyl chloride (obtained from Aldrich, Lot. No.112137) in THF (0.0125g, 0.0831 mM, 1.2 equiv.) was injected into theflask. Then 0.10 ml of an 11.6% (v/v) solution of triethylamine in THF(0.0084g, 0.0831 mM, 1.2 equiv.) was injected into the flask. Upon theaddition of triethylamine, the pale yellow reaction mixture becamecloudy. The reaction mixture was stirred for 2 hours at 0° and was thenallowed to warm to room temperature. After the mixture had stirred foran additional 1.5 hours at room temperature, 0.05 N HCl solution (1 ml)was added to the flask. Next conc. HCl reagent (3 drops) was added toadjust the reaction mixture to pH 1. This acidified reaction mixture wasstirred for 1 hour.

Ether and distilled water were then added to the reaction mixture. Theaqueous layer was removed and the ethereal layer was washed withdistilled water, dried (anh. Na₂ SO₄), filtered and concentrated to ayellow oil (0.036 g). Purification of the crude oil by thick layerchromatography (silica gel G, 1:24 MeOH-CHCl₃, 2-developments) affordedthe desired product (16) as a pale yellow oil (18.6 mg, 61%): IR bands3600-3420 (broad), 2935, 2870, 1735, 1655, 1460, 1375, 1310, 1125, 980cm⁻¹ ; pmr (CDCl₃) 0.89 (t), 1.06-1.75 (br m), 1.28 (t), 2.07 (br s),3.37 (br s), 3.58 (br s), 4.19 (q), 4.3-4.5 (m), 5.09-5.21 (m),5.23-6.25 (br m) δ; UVλ_(Max) ^(CHCl).sbsp.3 237 nm (log ε 3.87).

EXAMPLE 17 3(R)-(4(S),5(S)-Diacetoxy-1-[3-oxo-trans-1-octenyl]-cyclopentenyl)ethyl malonate(17)

Compound (16) (50 mg) in 5 ml of dioxane was treated with 40 mg of2,3-dichloro-5,6-dicyano-1,4-benzoquinone and stirred for 24 hours at50° under a nitrogen atmosphere. The reaction was cooled and filtered.The solids were washed with methylene chloride, and the washings and thefiltrate were evaporated. The desired (17) was purified by preparativetlc: UV λ_(Max) ^(EtOH) 265 nm (log ε 4.38); a new IR band at 1690 cm⁻¹; CIMS, MH⁺ 439.

EXAMPLE 181(R),5(R),8(R)-Acetoxy-4-(R)-carbethoxy-6-(3-oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0]oct-6-ene(18)

Compound (17) (0.050g) was dissolved in t-butyl alcohol and treated witha molar equivalent of potassium t-butoxide in t-butyl alcohol under anargon atmosphere at 40° for 24 hours. The reaction was cooled to roomtemperature and quenched by the addition of 10% aq. HCl solution (1 ml)and evaporated. Preparative tl-chromatography produced the desired (18)as a pale oil possessing an IR band at 1690 cm⁻¹ ; UVλ_(Max) ^(EtOH) 265nm; pmr 6.30 δ (br s); CIMS, MH⁺ 379.

EXAMPLE 191(R),5(R),8(R)-Acetoxy-6-(3-oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0]oct-6-ene(19)

Compound (18) (120 mg) was partially dissolved in anhydrous pyridine and6 equivalents of anhydrous (heat dried in vacuum) lithium iodide wasadded. After covering the mixture with a blanket of dry nitrogen gas,the mixture was refluxed for 3.5 hours. After cooling and pouring ontocrushed ice, the mixture was extracted with chloroform, dried overanhydrous sodium sulfate, filtered and evaporated. Compound (19) isobtained as an oil following preparative tlc. In addition to an IR bandat 1770 cm⁻¹ indicative of a λ-lactone and the absence of an ethylabsorption in the pmr spectrum, a UV maximum at 265 nm and a protonatedmolecular ion at MH⁺ = 307 characterize substance (19).

[Note it is a diastereoisomer of a compound described by P. Crabbe et.al., Tetrahedron Letters 3021 (1973)].

EXAMPLE 201(R),5(R)-6(3-oxo-trans-1-octenyl)-3-oxo-2-oxabicyclo[3.3.0]oct-6-ene(II)

Compound (19) (75 mg) is dissolved in 3 ml of glacial acetic acid, 50 mgof zinc dust is added, and the mixture is refluxed for 9 hours. Aftercooling, the compound (9) is isolated as described in Example 9 and isfound to have the same spectroscopic and chromatographic properties asstated previously.

What is claimed is:
 1. A cyclopentene of the formula: ##STR6## wherein Ris --Ch═CHCHO, --CHOH--CHOH--CH₃, --CH═CHCH₃ or --CH═Ch--CR₅ (CH₂)₄ CH₃with R₅ being ═ O or ##STR7## both R₁ are benzoyloxy or acetoxy; R₃ is##STR8## and R₇ is a loweralkyl moiety.
 2. The compound of claim 1wherein R is --Ch═CH--CR₅ --C₅ H₁₁ with R₅ representing ═ O or ##STR9##R₁ is benzoyloxy or acetoxy, R₃ is ##STR10##
 3. The compound of claim 2wherein said loweralkyl is ethyl and R₅ is oxo.
 4. The compound of claim3 wherein R₁ is benzoyloxy.
 5. The compound of claim 3 wherein R₁ isacetoxy.